EP0177783A2 - Expectorants comprising N-acetylneuraminic acid and its salts - Google Patents
Expectorants comprising N-acetylneuraminic acid and its salts Download PDFInfo
- Publication number
- EP0177783A2 EP0177783A2 EP85111414A EP85111414A EP0177783A2 EP 0177783 A2 EP0177783 A2 EP 0177783A2 EP 85111414 A EP85111414 A EP 85111414A EP 85111414 A EP85111414 A EP 85111414A EP 0177783 A2 EP0177783 A2 EP 0177783A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- acetylneuraminic acid
- sputum
- expectorant
- salt
- test
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003172 expectorant agent Substances 0.000 title claims abstract description 28
- 230000003419 expectorant effect Effects 0.000 title claims abstract description 28
- 150000003839 salts Chemical class 0.000 title abstract description 14
- SQVRNKJHWKZAKO-PFQGKNLYSA-N N-acetyl-beta-neuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-PFQGKNLYSA-N 0.000 title description 56
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 title description 55
- 229940066493 expectorants Drugs 0.000 title 1
- 206010036790 Productive cough Diseases 0.000 claims abstract description 46
- 208000024794 sputum Diseases 0.000 claims abstract description 36
- 210000003802 sputum Anatomy 0.000 claims abstract description 34
- 210000000254 ciliated cell Anatomy 0.000 claims description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 7
- 239000000443 aerosol Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052788 barium Inorganic materials 0.000 claims description 3
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 230000001886 ciliary effect Effects 0.000 abstract description 17
- 239000002253 acid Substances 0.000 abstract description 4
- 230000001737 promoting effect Effects 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 description 25
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- 210000004877 mucosa Anatomy 0.000 description 14
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- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 9
- 229960004373 acetylcholine Drugs 0.000 description 9
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- 230000028327 secretion Effects 0.000 description 5
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- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229960000195 terbutaline Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 3
- 238000011047 acute toxicity test Methods 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000007799 cork Substances 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000008263 liquid aerosol Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
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- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000003595 mist Substances 0.000 description 2
- 230000000420 mucociliary effect Effects 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 125000005629 sialic acid group Chemical group 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- GPCJIRWEMHGJQI-SGBOKBNOSA-N C(C)(=O)N[C@@H]1[C@H](CC(C([O-])=O)(O)O[C@H]1[C@H](O)[C@H](O)CO)O.[NH4+] Chemical compound C(C)(=O)N[C@@H]1[C@H](CC(C([O-])=O)(O)O[C@H]1[C@H](O)[C@H](O)CO)O.[NH4+] GPCJIRWEMHGJQI-SGBOKBNOSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000270934 Rana catesbeiana Species 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- JUGOREOARAHOCO-UHFFFAOYSA-M acetylcholine chloride Chemical compound [Cl-].CC(=O)OCC[N+](C)(C)C JUGOREOARAHOCO-UHFFFAOYSA-M 0.000 description 1
- 229960004266 acetylcholine chloride Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- -1 alkali metal salt Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 238000011597 hartley guinea pig Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 210000003254 palate Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229940098458 powder spray Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
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- 210000003437 trachea Anatomy 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
Definitions
- the present invention relates to an expectorant and a method of removing sputum by using the expectorant. More particularly, the invention is concerned with an expectorant made of N-acetylneuraminic acid and its pharmaceutically active salt having an effect of directly promoting ciliary motion while acting on the rheological property of sputum, as well as to a method of removing sputum by such an expectorant.
- Viscous secretion exists in the airway of the human body.
- the secretion has an important role in imparting suitable temperature and humidity to inhaled air.
- the matter generally referred to as "sputum” is constituted mainly by this secretion.
- sialic acids may serve as an effective expectorant which can be used locally.
- This invention has been accomplished through a study on the sputum-removing effect offered by N-acetylneuraminic acid and its salt, among the sialic acids.
- an object of the invention is to provide an expectorant mainly composed of N-acetylneuraminic acid or its salt, as well as a method of removing sputum by local dosage of the expectorant which acts on the rheological property of sputum and which directly promotes ciliary beat so as to facilitate the expectoration.
- the expectorant of the invention contains, as an effective component, an N-acetylneuraminic acid or its salt which is expressed by the following general formula:
- N-acetylneuraminic acid itself is a known compound, and its salt can be obtained by neutralizing this acid with a hydroxide or carbonate of an alkali metal or alkali earth metal and separating the corresponding alkali metal salt or alkali earth metal salt from the system.
- this compound is used in such a form as to permit the use of a known local administration method such as inhalation of the pulverized compound from an aerosol.
- N-acetylneuraminic acid and its salt as an expectorant is attributable to the following two functions: namely., physiological change for easier expectoration by the acting on the rheological property of /expectorant such as its fluidity, yield value, spinnability, stickiness, stress relaxing time and so forth, and promotion of sputum transportation by cilia through direct activation of ciliary beat of the cilia in the airway.
- the expectorant of the invention is used in the form of, for example, the following preparation.
- N-acetylneuraminic acid or its salt is well ground and mashed in an agate mortar to reduce it to a fine powder of a grain size ranging between 1 .and 20 microns. Lactose is then gradually mixed with the fine powder and diluted 10 to 20 fold. Then, 20 to 40 mg of the mixture is put in a capsule or envelope by a known method.
- a capsule is used for powdered aerosol, and an envelope is used for liquid aerosol.
- the expectorant is used as a powdered aerosol or liquid aerosol is determined on the basis of the symptoms of the patient.
- the dose is usually 0.5 to 5 mg/time.
- the expectorant should be administered at least two times a day but this may be changed if the symptoms warrant it.
- the expectorant is administered, when used in the form of a powdered aerosol, by means of a powder spray such as an insufflator or nebulizer, and when used as a liquid aerosol, by a liquid atomizer such as a nebulizer.
- the expectorant of the invention exhibits a superior sputum-removing effect when administered locally. Namely, it changes the property of sputum to ease expectoration by acting on the rheological property of sputum, e.g. yield value and viscosity. On the other hand, it directly activates the ciliated cells to promote expectoration by ciliary beat.
- Salts of lithium, potassium, sodium, organic ammonium, barium and magnesium of N-acetylneuraminic acid were prepared in the same way as that described above. Namely, the N-acetylneuraminic acid was neutralized with hydroxides or carbonates of these elements, followed by freeze-drying, thus the obtaining salts of/N-acetylneuraminic acid.
- N-acetylneuraminic acid and / calcium salt of N-acetylneuraminic acid provided by Kanto Ishiseiyaku Kabushiki Kaisha
- acetylcholine chloride furnished by Sigma Kabushiki Kaisha
- Mucociliary transport was measured by the particle transport method. After decapitation of a frog, the surface of the palatine mucosa was separated with minimized damage and fixed to a cork plate in a Petri dish which was then filled with 20 ml of Ringer's solution (trishydrochloric acid). The palatine mucosa was left in this state for 30 minutes before the commencement of measurement. For measurement, the Ringer's solution was removed and fine pieces of cork (capable of passing pharmaceutical sieve No. 5 but not capable of passing No. 6) were placed on the surface of the palatine mucosa, and the time (in seconds) required for the cork piece to move 1 cm was measured. The duration of movement, i.e., moving speed,-was measured also in the state immediately after the removal of the Ringer's solution or pharmaceutical solution.
- the duration of movement i.e., moving speed,-was measured also in the state immediately after the removal of the Ringer's solution or pharmaceutical solution.
- N-acetylneuraminic acid and its calcium salt causes an acceleration of the ciliary movement of palatine mucosa in a certain dose-dependency, as will be seen from Tables 1 and 3.
- N-acetylneuraminic acid and its calcium salt were confirmed as producing substantially the same ciliary movement promoting effect as the acetylcholine which has been known as being effective in the promotion of ciliary movement.
- N-acetylneuraminic acid and its calcium salt therefore, are expected to facilitate expectoration.
- the acetylcholine cannot be used as an expectorant because it causes undesirable effects such as bronchoconstriction and crinogenic action, although it promotes ciliary action.
- N-acetylneuraminic acid and its calcium salt can be used as an expectorant because they effectively promote ciliary action, without being accompanied by the detrimental effects produced by acetylcholine.
- Human ciliated cells were collected from a normal trachea by means of a branchoscope, the ciliated cells being separated by rubbing the bronchus while observing through the branchoscope, while the collection of frog ciliated cells was conducted by rubbing the palatine mucosa, without being specially careful.
- the cilium cells thus obtained were floated in Medium 199 (prepared by Gibco Company) and groups of ciliated cells, each consisting of several cells exhibiting rotary motion due to ciliary motion, were sucked up by a microsyringe in such a manner as to avoid damage to such cells, using observation through a phase contrast microscope.
- the groups of cells were transferred to a cover slip and one drop of chicken plasma (prepared by Difco Company) and one drop of 50% chicken embryo extract were added to the cells, thus forming clots.
- the rotary motion in the clots was recorded by means of a video recorder and the number of rotations per minute was measured.
- the agents were dissolved in the Medium 199 and were injected through a tube attached to a rose chamber.
- the states of rotary motion 5 minutes, 10 minutes and 15 minutes after the injection were recorded by means of a video recorder, and the number of revolutions was measured.
- N-acetylneuraminic acid was confirmed as also being effective in the promotion of the rotary motion of ciliated cells. It is considered that the rotary motion of the ciliated cells is transmitted into ciliary beat, thereby facilitating the expectoration. This clearly shows that N-acetylneuraminic acid will be effective as an expectorant.
- Mucociliary transport rate (hereinunder referred to as MTR), i.e. the rate of transport of sputum by cilia, was measured using frog palatine mucosa. At the same time, physicochemical properties of the sputum before and after application of N-acetylneuraminic acid were compared.
- the sputum used for the specimens was collected from 12 samples of patients suffering from chronic obstructive lung disease. N-acetylneuraminic acid was added to the specimen sputum in the ratios of 5 mg/ml sputum and 1 mg/ml sputum, and the specimen was left for 1 hour at 4 0 C before measurement. Sputum which had not been treated by N-acetylneuraminic acid was used as a comparison example. A palatine mucosa obtained from a decapitated frog head was kept at constant temperature and humidity until the mucus liquid of the frog itself depleted.
- the specimen sputum was placed on the dried palatine mucosa, and the speed of movement of the sputum was observed through a noumenal microscope, thus measuring the MTR.
- the pH value of the sputum was measured by means of an electronic model HM-SAp pH meter, while the spinnability was measured by a device developed by Nagaoka and Yamanaka (disclosed in Transactions of 2nd Symposium of Cough and sputum, published July 20, 1979).
- the yield value was measured by Dulfano's double-tube method which is shown in the American Review of Respiratory Diseases, Vol. 104, p88, 1971.
- a test was conducted to examine the acute toxicity of N-acetylneuraminic acid, using mice and rats, by means of intravenous injection, subcutaneous injection, per os inhalation.
- a small amount of activated carbon was added to an aqueous solution of N-acetylneuraminic acid and, under a flow of nitrogen gas, 1N sodium hydroxide was added to obtain a pH value of pH 7.3 to 7.8.
- the reacted solution was filtered using a filter of 0.2 ⁇ m and the filtrate was freeze-dried, forming a colorless powder of sodium salt of N-acetylneuraminic acid.
- Example 7 Using the sodium salt of N-acetylneuraminic acid obtained in Example 7, a test was conducted to confirm the above-mentioned effect in accordance with the same testing method as that of Example 1. The result of this test is shown in Table 6.
- Terbutaline showed a general tendency to increase a the rotation at/concentration of 10 -4 to 10- mg/ml.
- Acetylcholine showed an increase in the rotation in a certain dependency on the dose, at a concentration of between 10 -3 and 10- 2 mg/ml.
- the sodium salt of N-acetylneuraminic acid can be used as an expectorant as effectively as N-acetylneuraminic acid and its calcium salt.
- the sodium salt of N-acetylneuraminic acid can be used effectively as an expectorant which increases the viscosity of low viscosity sputum, such as purulent sputum which is difficult to expectorate,to a high level suitable for transport by cilia, thereby facilitating the expectoration.
- a test was conducted to examine the acute toxicity of the sodium salt of N-acetylneuraminic acid, in mice, rats, and administration guinea pig by means of/per os, subcutaneous injection, intravenous injection, intraperitoneal injection, and inhalation.
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- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Description
- The present invention relates to an expectorant and a method of removing sputum by using the expectorant. More particularly, the invention is concerned with an expectorant made of N-acetylneuraminic acid and its pharmaceutically active salt having an effect of directly promoting ciliary motion while acting on the rheological property of sputum, as well as to a method of removing sputum by such an expectorant.
- Viscous secretion exists in the airway of the human body. The secretion has an important role in imparting suitable temperature and humidity to inhaled air. The matter generally referred to as "sputum" is constituted mainly by this secretion.
- When its amount is moderate, the secretion in the airway is unconsciously swallowed or expelled with the breath, but usually is never expectorated. Thus, any expectoration suggests that there is something extraordinary in the respiratory system. On the other hand, accumulation of sputum to be expectorated in the airway is liable to cause an infection via the airway. From this point of view, the removal of sputum is a matter of great significance in the medical treatment of patients who suffer from a disease in the airway.
- Sputum is often very viscous and sticky so that expectoration causes the patient pain. In order to facilitate expectoration, therefore, amedicine which is referred to as "expectorant" has been used. This medicine is given in a general dosage orally or by injection. The expectorant thus administered serves to remove sputum by diluting the sputum through an increase in secretion by the mucosa of the airway, promotion of separation from the mucosa and enhancement of ciliary beat. This , however, involves various clinical problems concerning mechanism and effect.
- The present inventors have therefore made intensive studies and found that sialic acids may serve as
an effective expectorant which can be used locally. - This invention has been accomplished through a study on the sputum-removing effect offered by N-acetylneuraminic acid and its salt, among the sialic acids.
- Accordingly, an object of the invention is to provide an expectorant mainly composed of N-acetylneuraminic acid or its salt, as well as a method of removing sputum by local dosage of the expectorant which acts on the rheological property of sputum and which directly promotes ciliary beat so as to facilitate the expectoration.
-
- Figs. 1 and 2 are illustrations of the effect of N-acetylneuraminic acid on the rotation of ciliated cells; and the
- Figs. 3 and 4 are illustrations of /effect of terbutaline and acetylcholine on the rotation of ciliated cells.
- Brief Summary of the Invention:
-
- On condition of n = 1, Z represents hydrogen, lithium, potassium, sodium, ammonium, organic ammonium or an organic amine, whereas, on condition of n = 2,.Z represents calcium, barium or magnesium. The N-acetylneuraminic acid itself is a known compound, and its salt can be obtained by neutralizing this acid with a hydroxide or carbonate of an alkali metal or alkali earth metal and separating the corresponding alkali metal salt or alkali earth metal salt from the system.
- According to the invention, this compound is used in such a form as to permit the use of a known local administration method such as inhalation of the pulverized compound from an aerosol.
- The effect of N-acetylneuraminic acid and its salt as an expectorant is attributable to the following two functions: namely., physiological change for easier expectoration by the acting on the rheological property of /expectorant such as its fluidity, yield value, spinnability, stickiness, stress relaxing time and so forth, and promotion of sputum transportation by cilia through direct activation of ciliary beat of the cilia in the airway. These functions have been confirmed through an experiment in which the rotary motion of a cilium group before the application of N-acetylneuraminic acid or its salt was compared with that after the application, using cilium cells in the human airway, as well as through an experiment in which the sputum conveying property of cilia of frog palatine mucosa in the state after the application of the N-acetylneuraminic acid or its salt was compared with that before the application.
- In clinical use, the expectorant of the invention is used in the form of, for example, the following preparation.
- Example of Preparation:
- As the first step, N-acetylneuraminic acid or its salt is well ground and mashed in an agate mortar to reduce it to a fine powder of a grain size ranging between 1 .and 20 microns. Lactose is then gradually mixed with the fine powder and diluted 10 to 20 fold. Then, 20 to 40 mg of the mixture is put in a capsule or envelope by a known method. Preferably, a capsule is used for powdered aerosol, and an envelope is used for liquid aerosol.
- Whether the expectorant is used as a powdered aerosol or liquid aerosol is determined on the basis of the symptoms of the patient. The dose is usually 0.5 to 5 mg/time. The expectorant should be administered at least two times a day but this may be changed if the symptoms warrant it.
- The results of pharmacodynamic tests and acute toxicity tests showed that the number of dosage per day need not be limited.
- The expectorant is administered, when used in the form of a powdered aerosol, by means of a powder spray such as an insufflator or nebulizer, and when used as a liquid aerosol, by a liquid atomizer such as a nebulizer.
- The effect of the invention can be summarized as follows: the expectorant of the invention exhibits a superior sputum-removing effect when administered locally. Namely, it changes the property of sputum to ease expectoration by acting on the rheological property of sputum, e.g. yield value and viscosity. On the other hand, it directly activates the ciliated cells to promote expectoration by ciliary beat.
- Description will be now made hereinunder as to the way of synthesis of the compound of the invention, as well as the effect of the same, through preferred examples.
- 12 g of N-acetylneuraminic acid was dissolved in 150 ml of water to form an aqueous solution into which was stirred a saturated aqueous solution of ammonium until the solution becomes neutral (pH 6.7). The reaction solution was spontaneously filtrated and the residual was freeze-dried (one day) to form 13.2 g of white crystals.
- Qualitative Reaction of Ammonium Salt:
- According to General Testing Method of the Pharmacopeia of Japan, 10th Edition
- An excess amount of sodium hydroxide reagent was added to the ammonium salt and the mixture was heated. The mixture gave off an odor of ammonium and the fume changed a red litmus paper blue.
-
- 200 ml of distilled water was added to a mixture of N-acetylneuraminic acid 10.1 g (0.0323 mole) of/and 1.162 g (0.0162 mole) of calcium carbonate. The solution was stirred for 2' hours at room temperature until the calcium carbonate was completely dissolved (pH 6.55). The solution was filtered and the deposit was subjected to freeze-drying and decompression drying to form 11.0 g of colorless needle crystals.
- According to General Testing Method of Pharmacopeia of Japan 10th Edition
- (1) A yellowish red was observed in a flame reaction test of the calcium salt. an
- (2) A white precipitate was observed when /ammonium carbonate reagent was added to the calcium salt.
-
- (NMR(D20)ppm) 1.59 - 2.42 (m) 2.05(s), 3.71 (s) 3.99(s)
- Salts of lithium, potassium, sodium, organic ammonium, barium and magnesium of N-acetylneuraminic acid were prepared in the same way as that described above. Namely, the N-acetylneuraminic acid was neutralized with hydroxides or carbonates of these elements, followed by freeze-drying, thus the obtaining salts of/N-acetylneuraminic acid.
- Bull frogs (furnished by Saitama Test Animal) weighing 300 to 450 g were used regardless of sex.
- the
- N-acetylneuraminic acid and / calcium salt of N-acetylneuraminic acid (provided by Kanto Ishiseiyaku Kabushiki Kaisha), as well as acetylcholine chloride (furnished by Sigma Kabushiki Kaisha) were used as test substances.
- Mucociliary transport was measured by the particle transport method. After decapitation of a frog, the surface of the palatine mucosa was separated with minimized damage and fixed to a cork plate in a Petri dish which was then filled with 20 ml of Ringer's solution (trishydrochloric acid). The palatine mucosa was left in this state for 30 minutes before the commencement of measurement. For measurement, the Ringer's solution was removed and fine pieces of cork (capable of passing pharmaceutical sieve No. 5 but not capable of passing No. 6) were placed on the surface of the palatine mucosa, and the time (in seconds) required for the cork piece to move 1 cm was measured. The duration of movement, i.e., moving speed,-was measured also in the state immediately after the removal of the Ringer's solution or pharmaceutical solution.
- It was confirmed that N-acetylneuraminic acid and its calcium salt causes an acceleration of the ciliary movement of palatine mucosa in a certain dose-dependency, as will be seen from Tables 1 and 3.
- This result was substantially equal to that produced by acetylcholine (control) at concentrations of 10-5 and 10-4 g/mol, as will be seen from Table 2.
- N-acetylneuraminic acid and its calcium salt were confirmed as producing substantially the same ciliary movement promoting effect as the acetylcholine which has been known as being effective in the promotion of ciliary movement. N-acetylneuraminic acid and its calcium salt, therefore, are expected to facilitate expectoration. The acetylcholine, however, cannot be used as an expectorant because it causes undesirable effects such as bronchoconstriction and crinogenic action, although it promotes ciliary action. In contrast, N-acetylneuraminic acid and its calcium salt can be used as an expectorant because they effectively promote ciliary action, without being accompanied by the detrimental effects produced by acetylcholine.
- the Using ciliated cells from /human airway and frog palate, rotation of cell groups due to ciliary beat was observed before and after application of N-acetylneuraminic the acid and/calcium salt of N-acetylneuraminic acid, in order to confirm the effect of these agents on the ciliated cells.
- Human ciliated cells were collected from a normal trachea by means of a branchoscope, the ciliated cells being separated by rubbing the bronchus while observing through the branchoscope, while the collection of frog ciliated cells was conducted by rubbing the palatine mucosa, without being specially careful. The cilium cells thus obtained were floated in Medium 199 (prepared by Gibco Company) and groups of ciliated cells, each consisting of several cells exhibiting rotary motion due to ciliary motion, were sucked up by a microsyringe in such a manner as to avoid damage to such cells, using observation through a phase contrast microscope. The groups of cells were transferred to a cover slip and one drop of chicken plasma (prepared by Difco Company) and one drop of 50% chicken embryo extract were added to the cells, thus forming clots. The rotary motion in the clots was recorded by means of a video recorder and the number of rotations per minute was measured. The agents were dissolved in the
Medium 199 and were injected through a tube attached to a rose chamber. The states ofrotary motion 5 minutes, 10 minutes and 15 minutes after the injection were recorded by means of a video recorder, and the number of revolutions was measured. - With application of N-acetylneuraminic acid (10-4 to 10-1 mg/ml), the rotary motion of the cilium cells is gradually accelerated starting immediately after the application. 5 minutes, 10 minutes and 15 minutes after the application, plateaus were observed at application rates of 10-3 to 10-2 mg/ml. In these plateaus, the speed in revolutions per minute was about 25% higher than that in the
Medium 199, as will be seen from Figs. 1 and 2. It was confirmed also that the rotary motion of the cilium cells is increased by application of 10-3 to 3 x 10-2 mg/ml of terbutaline (5-[2-[(1.1-dimetylethyl) amino]-1-hydoxyethyl]-1,3-benzenediole), in a certain dependency to the dose. The effect was particularly remarkable 5 minutes after the application, as can be seen from Fig. 3. - It was confirmed also that the speed of rotary motion of the cilium cells is increased by the addition of 10-3 mg/ml and 3 x 10-3 mg/ml of acetylcholine. Speed peaks of the rotary motion were observed about 10 minutes and 5 minutes after the application when the amounts of addition were respectively, 10-3 mg/ml and 3 x 10-3 mg/ml. In both cases, the rotary motion stopped 13 minutes after the application.
- It was confirmed that terbutalin and acetylcholine, which are known as being effective in promoting ciliary beat, promote also the rotary motion of the cilium cells. N-acetylneuraminic acid was confirmed as also being effective in the promotion of the rotary motion of ciliated cells. It is considered that the rotary motion of the ciliated cells is transmitted into ciliary beat, thereby facilitating the expectoration. This clearly shows that N-acetylneuraminic acid will be effective as an expectorant.
- Mucociliary transport rate (hereinunder referred to as MTR), i.e. the rate of transport of sputum by cilia, was measured using frog palatine mucosa. At the same time, physicochemical properties of the sputum before and after application of N-acetylneuraminic acid were compared.
- The sputum used for the specimens was collected from 12 samples of patients suffering from chronic obstructive lung disease. N-acetylneuraminic acid was added to the specimen sputum in the ratios of 5 mg/ml sputum and 1 mg/ml sputum, and the specimen was left for 1 hour at 40C before measurement. Sputum which had not been treated by N-acetylneuraminic acid was used as a comparison example. A palatine mucosa obtained from a decapitated frog head was kept at constant temperature and humidity until the mucus liquid of the frog itself depleted. The specimen sputum was placed on the dried palatine mucosa, and the speed of movement of the sputum was observed through a noumenal microscope, thus measuring the MTR. The pH value of the sputum was measured by means of an electronic model HM-SAp pH meter, while the spinnability was measured by a device developed by Nagaoka and Yamanaka (disclosed in Transactions of 2nd Symposium of Cough and sputum, published July 20, 1979). The yield value was measured by Dulfano's double-tube method which is shown in the American Review of Respiratory Diseases, Vol. 104, p88, 1971.
- As shown in Table 4, five out of six samples treated with 1 mg/ml of N-acetylneuraminic acid showed a reduction in pH value (pH 7.31 ± 0.40), while the remaining one sample showed a slight increase in pH value. Increase in the yield value was observed in three samples, while three samples showed a reduction. The yield value was unchanged in the remaining one sample. As to the spinnability, five samples showed a reduction, while one sample showed a slight increase. The samples which showed reduction in the spinnability exhibited a tendency to increased MTR.
- A test was conducted to examine the acute toxicity of N-acetylneuraminic acid, using mice and rats, by means of intravenous injection, subcutaneous injection, per os inhalation.
- (1) Test Animals
- ICR mice 6 weeks old
- SD rats 6 weeks old (7 weeks old in case -of inhalation)
- (2) Application Density 13 to 15% (W/V) dissolved in distilled water
- (3) Number of Test Animals per
Group 10 - (4)
Observation Period 14 days - (5) Method of Calculation of LD50
- By Litchfield-Wilcoxon method
- The result of the test is shown in Table 5 below.
- Inhalation was conducted by 1-hr exposure to mist. Values in parentheses show 95% reliability level.
- A small amount of activated carbon was added to an aqueous solution of N-acetylneuraminic acid and, under a flow of nitrogen gas, 1N sodium hydroxide was added to obtain a pH value of pH 7.3 to 7.8. The reacted solution was filtered using a filter of 0.2 µm and the filtrate was freeze-dried, forming a colorless powder of sodium salt of N-acetylneuraminic acid.
- 1R 3400 cm-, 2937 cm-
- 1660 to 1620 cm-1, 1560 cm-1 decomposition point about 140 - 185°C (decomposition with foaming)
- lH-400MHz (D20)
- 1,807 (dd, H3ax)
- 2,205 (dd, H3eq)
- 4,022 (m, H4)
- 3,901 (t, H5)
- 3,973 (d, H6)
- 3,501 (d, H7)
- 3,747 (m, H8) 3,598 (dd, H9')
- 3,831 (dd, H9) 2,041 (s, Ac-5)
- Using the sodium salt of N-acetylneuraminic acid obtained in Example 7, a test was conducted to confirm the above-mentioned effect in accordance with the same testing method as that of Example 1. The result of this test is shown in Table 6.
- From Table 6, it will be seen that the sodium salt of N-acetylneuraminic acid caused acceleration of the MTR of the frog palatine mucosa in a certain dependency on the dose. The result was subtantially equivalent to that of the acetylcholine (comparison agent) at a concentration of 10-4 mg/ml. This suggests that the sodium salt of N-acetylneuraminic acid produces an effect similar to that produced by the above-described N-acetylneuraminic acid and its calcium salt.
- A test was conducted to examine the above-mentioned effect by using sodium salt of N-Acetylneuraminic Acid, in accordance with the same testing method as that of Example 2. The result of this test is shown in Table 7 which shows the following facts.
- A significant number of rotations was observed upon application of 10-3 mg/ml of sodium salt of N-acetylneuraminic acid.
- Terbutaline showed a general tendency to increase a the rotation at/concentration of 10-4 to 10- mg/ml.
- Acetylcholine showed an increase in the rotation in a certain dependency on the dose, at a concentration of between 10-3 and 10-2 mg/ml.
- From these facts, it is understood that the sodium salt of N-acetylneuraminic acid can be used as an expectorant as effectively as N-acetylneuraminic acid and its calcium salt.
-
- The effect of the sodium salt of N-acetylneuraminic acid on sputum was examined in accordance with the testing method explained in connection with Example 5. The result of this test is shown in Table 8.
- From Fig. 8, it will be seen that the samples treated with the sodium salt of N-acetylneuraminic acid (1 mg/ml sputum) showed a significant increase in pH value and MTR. Although the spinnability was generally increased, a reduction was observed with regard to the yield value.
- From these facts, it is understood that the sodium salt of N-acetylneuraminic acid can be used effectively as an expectorant which increases the viscosity of low viscosity sputum, such as purulent sputum which is difficult to expectorate,to a high level suitable for transport by cilia, thereby facilitating the expectoration.
- A test was conducted to examine the acute toxicity of the sodium salt of N-acetylneuraminic acid, in mice, rats, and administration guinea pig by means of/per os, subcutaneous injection, intravenous injection, intraperitoneal injection, and inhalation.
- (1) Test Animals
ICR mice 6 weeks old SD rats 6 weeks old Hartley guinea pig 6 weeks old - (2)
Application Density 20% (W/V) dissolved in distilled water - (3) Number of Test Animals per
Level 10 - (4)
Observation Period 14 days - (5) Method of Calculation of LD50 By Probit method The result of the test is shown in Table 9 below.
Inhalation was conducted by 1-hr exposure to mist. Values in parentheses show 95% reliability limit.
Claims (3)
wherein, on condition of n = 1, Z represents hydrogen, lithium, potassium, sodium, ammonium, organic ammonium or organic amine, whereas on condition of n = 2, Z represents calcium, barium or magnesium, as an effective component.
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JP59189950A JPS6168418A (en) | 1984-09-11 | 1984-09-11 | Expectorant |
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US (1) | US4698332A (en) |
EP (2) | EP0429430B1 (en) |
JP (1) | JPS6168418A (en) |
KR (1) | KR880001234B1 (en) |
CN (1) | CN85108388B (en) |
AT (2) | ATE111738T1 (en) |
AU (1) | AU582584B2 (en) |
CA (1) | CA1246452A (en) |
DE (2) | DE3587928T2 (en) |
DK (1) | DK165046C (en) |
ES (1) | ES8606323A1 (en) |
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EP0281067A2 (en) * | 1987-03-06 | 1988-09-07 | Mect Corporation | N-acetyl-3-fluoro-neuraminic acid derivatives and preparation thereof |
EP0296620A2 (en) * | 1987-06-25 | 1988-12-28 | Mect Corporation | Use of N-acetylneuraminic-acid salts for the preparation of a medicament for decongesting nasal mucous membranes |
WO1995017898A1 (en) * | 1993-12-30 | 1995-07-06 | Novadex Pharmaceuticals Limited | A method of preventing or reducing the risk of infection by bacterial pathogens utilizing simple and conjugated dextrans |
WO1995022993A1 (en) * | 1994-02-25 | 1995-08-31 | Central Sydney Area Health Service | Method and device for the provocation of air passage narrowing and/or the induction of sputum |
CN107207552A (en) * | 2015-01-28 | 2017-09-26 | 协和发酵生化株式会社 | The crystal and its manufacture method of N n acetylneuraminic acid n ammonium salt anhydrides |
EP3178833A4 (en) * | 2014-07-30 | 2017-12-27 | Kyowa Hakko Bio Co., Ltd. | Crystal of alkali metal n-acetylneuraminate anhydrate, and method for producing same |
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JPS61289037A (en) * | 1985-06-14 | 1986-12-19 | Mect Corp | Novel expectorant |
GB8519416D0 (en) * | 1985-08-01 | 1985-09-04 | Unilever Plc | Oligosaccharides |
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US5843445A (en) * | 1987-06-24 | 1998-12-01 | Autoimmune, Inc. | Method of treating rheumatoid arthritis with type II collagen |
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US5856446A (en) * | 1995-07-07 | 1999-01-05 | Autoimmune Inc. | Method of treating rheumatoid arthritis with low dose type II collagen |
AUPQ275799A0 (en) | 1999-09-10 | 1999-10-07 | Luminis Pty Limited | Recombinant bacterium expressing an oligosaccharide receptor mimic |
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- 1985-09-06 US US06/773,036 patent/US4698332A/en not_active Expired - Fee Related
- 1985-09-10 CA CA000490308A patent/CA1246452A/en not_active Expired
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- 1985-09-10 DE DE3587928T patent/DE3587928T2/en not_active Expired - Fee Related
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- 1985-09-10 EP EP91100080A patent/EP0429430B1/en not_active Expired - Lifetime
- 1985-09-10 ZA ZA856905A patent/ZA856905B/en unknown
- 1985-09-10 AT AT85111414T patent/ATE111738T1/en not_active IP Right Cessation
- 1985-09-10 FI FI853456A patent/FI83963C/en not_active IP Right Cessation
- 1985-09-10 HU HU883140A patent/HU198733B/en unknown
- 1985-09-10 HU HU853417A patent/HU197515B/en not_active IP Right Cessation
- 1985-09-10 DE DE91100080T patent/DE3587587T2/en not_active Expired - Fee Related
- 1985-09-10 AT AT91100080T patent/ATE94396T1/en not_active IP Right Cessation
- 1985-09-10 KR KR1019850006606A patent/KR880001234B1/en not_active IP Right Cessation
- 1985-09-10 EP EP85111414A patent/EP0177783B1/en not_active Expired - Lifetime
- 1985-09-11 DK DK413785A patent/DK165046C/en not_active IP Right Cessation
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EP0281067A2 (en) * | 1987-03-06 | 1988-09-07 | Mect Corporation | N-acetyl-3-fluoro-neuraminic acid derivatives and preparation thereof |
EP0281067A3 (en) * | 1987-03-06 | 1988-12-14 | Mect Corporation | N-acetyl-3-fluoro-neuraminic acid derivatives and preparation thereof |
EP0296620A2 (en) * | 1987-06-25 | 1988-12-28 | Mect Corporation | Use of N-acetylneuraminic-acid salts for the preparation of a medicament for decongesting nasal mucous membranes |
EP0296620A3 (en) * | 1987-06-25 | 1989-10-04 | Mect Corporation | N-acetylneuraminic-acid salts as repairing agents for cells and tissues |
US5015631A (en) * | 1987-06-25 | 1991-05-14 | Mect Corporation | Repairing agent for cells and tissues |
AU617111B2 (en) * | 1987-06-25 | 1991-11-21 | Mect Corporation | Repairing agent for cells and tissues |
WO1995017898A1 (en) * | 1993-12-30 | 1995-07-06 | Novadex Pharmaceuticals Limited | A method of preventing or reducing the risk of infection by bacterial pathogens utilizing simple and conjugated dextrans |
US5514665A (en) * | 1993-12-30 | 1996-05-07 | University Of British Columbia | Method of preventing or reducing the risk of infection by bacterial pathogens utilizing simple and conjugated dextrans |
WO1995022993A1 (en) * | 1994-02-25 | 1995-08-31 | Central Sydney Area Health Service | Method and device for the provocation of air passage narrowing and/or the induction of sputum |
US5817028A (en) * | 1994-02-25 | 1998-10-06 | Central Sydney Area Health Service | Method and device for the provocation of air passage narrowing and/or the induction of sputum |
CN1075737C (en) * | 1994-02-25 | 2001-12-05 | 悉尼中部地区健康服务中心 | Method and device for the provocation of air passage narrowing and/or the induction of sputum |
EP3178833A4 (en) * | 2014-07-30 | 2017-12-27 | Kyowa Hakko Bio Co., Ltd. | Crystal of alkali metal n-acetylneuraminate anhydrate, and method for producing same |
CN107207552A (en) * | 2015-01-28 | 2017-09-26 | 协和发酵生化株式会社 | The crystal and its manufacture method of N n acetylneuraminic acid n ammonium salt anhydrides |
EP3252065A4 (en) * | 2015-01-28 | 2018-09-19 | Kyowa Hakko Bio Co., Ltd. | Crystals of n-acetylneuraminic acid ammonium salt anhydrate, and method for producing same |
CN107207552B (en) * | 2015-01-28 | 2021-03-26 | 协和发酵生化株式会社 | Crystal of N-acetylneuraminic acid ammonium salt anhydride and process for producing the same |
Also Published As
Publication number | Publication date |
---|---|
DE3587587T2 (en) | 1994-03-31 |
ES546840A0 (en) | 1986-04-16 |
ATE111738T1 (en) | 1994-10-15 |
CN85108388B (en) | 1988-08-24 |
ATE94396T1 (en) | 1993-10-15 |
EP0429430A3 (en) | 1991-10-23 |
CN85108388A (en) | 1987-06-03 |
AU582584B2 (en) | 1989-04-06 |
US4698332A (en) | 1987-10-06 |
HUT40804A (en) | 1987-02-27 |
DE3587928D1 (en) | 1994-10-27 |
EP0177783B1 (en) | 1994-09-21 |
ZA856905B (en) | 1986-06-25 |
HU198733B (en) | 1989-11-28 |
ES8606323A1 (en) | 1986-04-16 |
FI83963C (en) | 1991-09-25 |
HU197515B (en) | 1989-04-28 |
AU4719985A (en) | 1986-03-20 |
FI853456L (en) | 1986-03-12 |
KR880001234B1 (en) | 1988-07-12 |
DK165046C (en) | 1993-02-22 |
JPS6168418A (en) | 1986-04-08 |
EP0429430B1 (en) | 1993-09-15 |
EP0177783A3 (en) | 1989-02-22 |
EP0429430A2 (en) | 1991-05-29 |
JPS6328411B2 (en) | 1988-06-08 |
DE3587587D1 (en) | 1993-10-21 |
FI853456A0 (en) | 1985-09-10 |
FI83963B (en) | 1991-06-14 |
DK413785D0 (en) | 1985-09-11 |
CA1246452A (en) | 1988-12-13 |
DE3587928T2 (en) | 1995-01-26 |
DK413785A (en) | 1986-03-12 |
DK165046B (en) | 1992-10-05 |
KR860002525A (en) | 1986-04-26 |
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